Purification methods

ABSTRACT

The invention relates to novel processes for the purification of radiolabelled tracers, using a solid-support bound scavenger group. The general concept being illustrated by the scheme:

The present invention relates to novel processes for the purification ofradiolabelled tracers, in particular for purification of ¹⁸F- and¹¹C-labelled compounds which may be suitable for use as PositronEmission Tomography (PET) radiotracers or for radio-iodinated compoundswhich may be suitable for use in PET or SPECT imaging or inradiotherapy. Automated radiosynthesis apparatus, and disposable orremovable cassettes therefor, adapted to perform the purificationprocesses are also claimed.

Radiosynthesis of compounds of clinical interest often employsnon-radioactive organic precursors in amounts which are in large excessrelative to the amount of radiolabelling agent used. Excess precursorsmust be removed from the reaction mixture before the radiolabelledcompound can be used clinically, this is conventionally done by achromatographic procedure such as high performance liquid chromatography(HPLC). Given the limited half-life of most clinically usefulradioisotopes, it is desirable to complete the radiosynthesis andpurification as rapidly as possible. For example, ¹⁸F has a half-life of110 minutes and ¹⁸F-labelled tracers for PET are therefore synthesisedand purified within one hour of clinical use. Therefore, there exists aneed for purification techniques which are rapid and efficient.

The present invention provides processes for separating radiolabelledcompounds from their precursors rapidly and chemoselectively.

According to a general aspect of the invention, there is provided aprocess for purifying a radiolabelled product which comprises use of asolid-support bound scavenger group of formula (IV):

wherein Z is a scavenger group and SP is a solid support.

In a further aspect of the invention, there is provided a processcomprising the steps of:(a) contacting a solution-phase mixture of a radiolabelled product offormula (III) and excess precursor of formula (I):

wherein XY is a functional group and R* is a radioisotope orradiolabelled portion; with a compound of formula (IV):

wherein Z is a scavenger group;such that the compounds of formulae (IV) and (I) may form a covalentbond to each other;(b) separation of purified radiolabelled product of formula (III) in thesolution phase.

Suitably, the radiolabelled product of formula (III) contains an¹⁸F-label and is, for example 2-fluoro-2-deoxy-D-glucose ([¹⁸F]-FDG),6-fluoro-L-DOPA ([¹⁸F]-FDOPA), 3′-deoxy-3′-fluorothymidine ([¹⁸F]-FLT),[¹⁸F]fluorotyrosine, 5-[¹⁸F]fluorouracil, 5-[¹⁸F]fluorocytosine,2-(1,1-dicyanopropen-2-yl)-6-(2-fluoroethyl)-methylamino)-naphthalene([¹⁸F]-FDDNP), 2-, 5-, and 6-fluoro (2(S)-azetinylmethoxy)pyridines,N-succinimidyl-4-[¹⁸F]fluorobenzoate ([¹⁸F]-SFB), an ¹⁸F-labelled aminoacid such as [¹⁸F]-1-amino-3-fluorocyclobutane-1-carboxylic acid([¹⁸F]-FACBC), an [¹⁸F]-labelled benzothiazole such as those describedin international patent application WO 02/16333, a [¹⁸F]fluorotropanesuch as 2β-carbomethoxy-3β-(4-[¹⁸F]fluorophenyl)tropane ([¹⁸F]CFT) orN-[¹⁸F]fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl)nortropane([¹⁸F]FP-CIT), [¹⁸F]FETNIM, [¹⁸F]dopamine, an ¹⁸F-labelled peptide forexample somatostatin analogues, such as octreotide, bombesin, vasoactiveintestinal peptide, chemotactic peptide analogues, α-melanocytestimulating hormone, neurotensin, Arg-Gly-Asp peptide and its analogues,human pro-insulin connecting peptide, endothelin, angiotensin andformyl-norleucyl-leucyl-phenylalanyl-norleucyl-tyrosyl-lysine, moresuitably Arg-Gly-Asp peptide and its analogues, such as those describedin international patent applications WO 01/77415 and WO 03/006491, or aprotected derivative of any thereof.

Alternatively, the radiolabelled product of formula (III) contains a¹¹C-label and is, for example, [¹¹C]raclopride, [¹¹C-carboxyl]L-DOPA,[¹¹C-carboxyl]5-hydroxytryptophan, [¹¹C]-WAY-100635, [¹¹C]-deprenyl,[¹¹C]phenylephrine, [¹¹C]FLB457, [¹¹C]SCH23390, [¹¹C]SCH39166,[¹¹C]-NNC112, [¹¹C]NNC756, [¹¹C]MDL100907, [¹¹C]DSAB, [¹¹C]PK11195,[¹¹C]GR205171, [¹¹C]RTI-32, [¹¹C]CIT, [¹¹C]CFT, [¹¹C]flumazenil,[¹¹C]-diprenorphine, [¹¹C]-metomidate, [¹¹C]SCH442416, [¹¹C]carfentanil,or a ¹¹C-labelled benzothiazole such as those described in internationalpatent application WO 02/16333, or a protected derivative of anythereof.

Alternatively, the radiolabelled product of formula (III) contains aradioiodine label such as ¹³¹I, ¹²³I, ¹²⁴I, ¹²²I or ¹²⁵I, and is forexample,2-beta-carbomethoxy-3-beta-(4-iodophenyl)-8-(3-fluoropropyl)-nortropaneor a protected derivative thereof.

The radiolabelled product of formula (III) comprises a vector portionbeing a molecular fragment having with an affinity for a givenbiological target (such as a modified drug pharmacaphore or peptide) anda radioisotope or radiolabelled portion represented by R*.

The precursor of formula (I) comprises the same vector portion as theradiolabelled product of formula (III) but bears a functional group —XYas described below.

Many radiosyntheses involve radioalkylation such as [¹¹C]alkylation, orradiohalogenation such as [¹⁸F]fluorination or [¹⁸F]fluoroalkylation, ofprecursors of formula (I). Treatment of the precursor with aradioisotope or radiolabelling agent of formula (II) gives rise to amixture containing the desired radiolabelled product of formula (III)and excess unreacted precursor of formula (I). The precursor of formula(I) therefore contains a functional group —XY which is capable ofreacting with the radioisotope or radiolabelling agent of formula (II)shown in scheme I. The functional group —XY is suitably a leaving groupsuch as a sulphonate ester preferably the mesyl, tosyl, nosyl or is atrimethylammonium salt or is a functional group which can reactsite-specifically with a moiety on the radiolabelling agent of formula(II) to form a stable covalent bond and is preferably selected from thegroups aldehydes, ketones, aminooxy, hydrazides, hydrazines,alpha-haloacetyl and thiol.

In the compound of formula (IV), the scavenger group Z is suitably anisocyanate, isothiocyanate, thiol, hydrazine, hydrazide, aminooxy,1,3-dipole, aldehyde or ketone, such as those described in the morespecific aspects of the invention below.

In the compounds of formulae (IV) and in the following more specificaspects of the invention, the solid support represented by SP, may beany suitable solid-phase support which is insoluble in any solvents tobe used in the process but to which the Linker and/or scavenger group Zcan be covalently bound. Examples of suitable Solid Support includepolymers such as polystyrene (which may be block grafted, for examplewith polyethylene glycol), polyacrylamide, ring-opening metathesispolymerisation (ROMP) polymer, or polypropylene or glass or siliconcoated with such a polymer. The solid support may also be sepharosebased modified with suitable functional groups or derived from otherknown polymeric chromatographic media including ion exchange resins orC18 reverse-phase media. The solid support may be in the form of smalldiscrete particles such as beads or pins, or as a coating on the innersurface of a cartridge or on a microfabricated vessel.

In the compounds of formulae (IV) and in the following more specificaspects of the invention, the “Linker” may be any suitable organic groupwhich serves to space the scavenger group Z sufficiently from the solidsupport structure so as to maximise reactivity. Suitably, the Linkercomprises zero to four aryl groups (suitably phenyl) and/or a C₁₋₆ alkylor C₁₋₆ haloalkyl (suitably C₁₋₆ fluoroalkyl), and optionally one tofour additional functional groups such as an amide or sulphonamidegroups. In a preferred embodiment the linker is a polyethylene glycolcontaining moiety.

Compounds of formula (IV) may be prepared by methods known to the personskilled in the art (for a review of such methods, see Stabile-Harris andCiampoli; Laboratory Automation in the Chemical Industries, 111-32(2002)) or are available commercially, for example from Novabiochem(Merck Biosciences Ltd, Nottingham, UK) or from Argonaut (Mid Glamorgan,UK)

The purification may be performed by mixing the solid-support boundscavenger group of formula (IV) with a solution-phase mixture comprisinga radiolabelled product of formula (III) in a container and thenseparating the resulting solid-phase by filtration. Alternatively, andparticularly suitably when the solid-support bound scavenger group offormula (IV) is used within an automated synthesis apparatus, thesolid-support bound scavenger group of formula (IV) may be contained ina vessel through which the solution-phase mixture comprising aradiolabelled product of formula (III) is passed. The solution-phasemixture comprising a radiolabelled product of formula (III) may bepassed through the solid-support bound scavenger group of formula (IV)as a continuous flow, for example at a flow rate of from 0.1 ml/min to100 ml/min, or in batches, so as to permit sufficient residence time onthe solid-phase for the purification to occur. As would be understood bythe person skilled in the art, the solid-support bound scavenger groupof formula (IV) may be held in any suitable vessel such as a plastic ormetal column, cartridge, or syringe barrel. The purification isconveniently performed at ambient temperature, but use of non-extremeelevated temperature (for example up to 120° C., but preferably up toaround 80° C.) can increase efficiency of the extraction. If thetemperature is too high, stability of the solid-support bound scavengergroup of formula (IV) and/or radiolabelled product of formula (III) maybe compromised.

In a further aspect of the invention, there is provided a process forpurifying a radiolabelled product which comprises use of a solid-supportbound isocyanate or isothiocyanate scavenger group. This processcomprises the steps of:(a) contacting a solution-phase mixture of a radiolabelled product offormula (IIIa) and excess precursor of formula (Ia):

wherein R¹ is C₁₋₆ alkyl and R* is [¹¹C]-C₁₋₆alkyl, such as —¹¹CH₃ or[¹⁸F]fluoro C₁₋₆ alkyl or [¹⁸F]fluoro C₆₋₁₂ aryl;with a compound of formula (IVa):

wherein R² is oxygen or sulphursuch that the compounds of formulae (IVa) and (Ia) may form a covalentbond to each other; and(b) separation of purified radiolabelled product of formula (IIIa) inthe solution phase.

The compounds of formula (IVa) and (Ia) react to form the correspondingurea or thiourea of formula (Va):

wherein R¹ and R² are as defined for the compounds of formulae (Ia) and(IVa) respectively.

The purification process using a compound of formula (IVa) may beperformed at a non-extreme temperature such as 10 to 120° C., suitablyat ambient temperature to 80° C. and using an inert solvent such asxylene, N,N-dimethylformamide (DMF) or chloroform.

In this aspect of the invention, the compound of formula (IIIa) issuitably a ¹¹C-labelled tertiary amine such as[¹¹C—CH₃]-2-Pyridin-4-yl-quinoline-8-carboxylic acid(2-dimethylamino-ethyl)-amide, [N-¹¹C-methyl]dimethylphenethylamine, or[¹¹C]DASB, and the precursor of formula (Ia) is the correspondingsecondary amine such as 2-pyridin-4-yl-quinoline-8-carboxylic acid(2-methylamino-ethyl)-amide.

In a further aspect of the invention, there is provided a process forpurifying a radiolabelled product which comprises use of a solid-supportbound thiol scavenger group. This process comprises the steps of:(a) contacting a solution-phase mixture of a radiolabelled product offormula (IIIb) and excess precursor of formula (Ib):

wherein either(i) the functional group —X^(b)Y^(b) in the compound of formula (Ib) is—OSO₂R³ wherein R³ is C₁₋₁₅ alkyl or C₁₋₁₀ alkylaryl and R³ isoptionally substituted by halo (preferably fluoro), for example R³ ismethyl, para-toluene, trifluoromethyl, and R*^(b) in the compound offormula (IIIb) is a radiohalogen such as radiofluoro (for example ¹⁸F)or radioiodo (such as ¹²³I, ¹²⁴I or ¹²⁵I) or radiobromo (such as ⁷⁶Br);or(ii) the functional group —X^(b)Y^(b) in the compound of formula (Ib) is—C(O)CH₂Cl and R*^(b) in the compound of formula (IIIb) is—S-L^(b)-^(n)F wherein L^(b) is a C₁₋₃₀ hydrocarbyl linker groupoptionally including 1 to 10 heteroatoms; and^(n)F is a radioisotope of fluorine such as ¹⁸F;with a compound of formula (IVb):

wherein R⁴ is hydrogen;such that the compounds of formulae (IVb) and (Ib) may form a covalentbond to each other;(b) separation of purified radiolabelled product of formula (IIIb) inthe solution phase.

The compounds of formula (IVb) and (Ib) react to form the correspondingcompound of formula (Vbi or Vbii):

The purification process using a compound of formula (IVb) may beperformed at a non-extreme temperature such as 10 to 120° C., suitablyat ambient temperature to 80° C. and using an inert solvent such asxylene, N,N-dimethylformamide (DMF), DMSO, acetonitrile or chloroform.Preferably the solvent is an aqueous buffer or a mixture of acetonitrileand water or alcohol and water.

In a further aspect of the invention, there is provided a process forpurifying a radiolabelled product which comprises use of a solid-supportbound amino scavenger group. This process comprises the steps of:(a) contacting a solution-phase mixture of a radiolabelled product offormula (IIIc) and excess precursor of formula (Ic):

wherein the functional group —X^(c)Y^(c) in the compound of formula (Ic)is an aldehyde or ketone and R*^(c) in the compound of formula (IIIc) is═N—W-Linker-F where W is C₁₋₁₅ alkyl or C₇₋₁₅ aryl, with a compound offormula (IVc):

wherein Z^(c) is selected from —NH₂, hydrazine, hydrazide, aminooxy,phenylhydrazines, semicarbazide, or thiosemicarbazide;such that the compounds of formulae (IVc) and (Ic) may form a covalentbond to each other; and(b) separation of purified radiolabelled product of formula (IIIc) inthe solution phase.

The compounds of formula (IVc) and (Ic) react to form the correspondingcompound of formula (Vc):

wherein A is hydrogen, C₁₋₆alkyl or aryl (such as phenyl) and B is—CO—NH—, —NH—, —O—, —NHCONH—, or —NHCSNH—.

In this aspect of the invention, compounds of the formula (IIc) have theformula NH₂—W-Linker-F where W is as described previously and F ispreferably ¹⁸F and the compound of formula (IIIc) is suitably a¹⁸F-labelled compound such as a peptide or drug substance and theprecursor of formula (Ic) is the corresponding aldehyde or ketone.

The purification process using a compound of formula (IVc) may beperformed at a non-extreme temperature such as 10 to 120° C., suitablyat ambient temperature to 80° C. and using an inert solvent such asxylene, N,N-dimethylformamide (DMF), DMSO, acetonitrile, or chloroform.Preferably the solvent is an aqueous buffer or a mixture ofacetonitrile: water or alcohol and water.

In a further embodiment of this aspect of the invention, the functionalgroup —X^(c)Y^(c) in the compound of formula (Ic) is —OSO₂R³ wherein R³is C₁₋₁₅ alkyl or C₁₋₁₀ alkylaryl and R³ is optionally substituted byhalo (preferably fluoro), for example R³ is methyl, para-toluene,trifluoromethyl; and the purification is effected using a compound offormula (IVci):

where W is selected from C₁₋₁₅ alkyl or C₇₋₁₅ aryl, —NH—, —NH—CO— or —O—and the linker is as described previously such that compounds of formula(Ic) and (IVci) form a covalent bond to each other.

The compounds of formula (IVci) and (Ic) react to form the correspondingcompound of formula (Vci):

wherein W is as defined for the compound of formula (IVci).

In a further aspect of the invention, there is provided a process forpurifying a radiolabelled product which comprises use of a solid-supportbound aldehyde or ketone scavenger group. This process comprises thesteps of:(a) contacting a solution-phase mixture of a radiolabelled product offormula (IIId) and excess precursor of formula (Id):

wherein the functional group —X^(d)Y^(d) in the compound of formula (Id)is an amine, hydrazine, hydrazide, aminooxy, phenylhydrazine, orsemicarbazide, thiosemicarbazide group and R*^(d) in the compound offormula (IIId) is ═CH-Linker-F where the linker comprises an alkyl, arylor polyethylene glycol component;with a compound of formula (IVd):

wherein Z^(d) is an aldehyde or ketone moiety;such that the compounds of formulae (IVd) and (Id) may form a covalentbond to each other; and(b) separation of purified radiolabelled product of formula (IIId) inthe solution phase.

The compounds of formula (Id) and (IVd) react to give compounds offormula (Vd):

wherein A is hydrogen, C₁₋₆alkyl or aryl (such as phenyl) and B is—CO—NH—, —NH—, —O—, —NHCONH—, or —NHCSNH—.

The purification process using a compound of formula (IVd) may beperformed at a non-extreme temperature such as 10 to 120° C., suitablyat ambient temperature to 80° C. and using an inert solvent such asxylene, N,N-dimethylformamide (DMF), DMSO, acetonitrile or chloroform.Preferably the solvent is an aqueous buffer or a mixture of acetonitrileand water or alcohol and water.

In this aspect of the invention, the compound of formula (IIId) issuitably a ¹⁸F-labelled compound such as a peptide or drug and theprecursor of formula (Id) is suitably a modified peptide or drugcarrying an aminooxy (NH₂—O—), hydrazide or hydrazine moiety.

One particular compound of formula (IVd) which may be useful in thisaspect of the invention, having a high loading of ketone scavenginggroup may be based on a ring-opening metathesis polymerisation (ROMP)polymer backbone. One of the main advantages of ROMP polymers is that inprinciple every monomer unit carries a functional group and should givemuch higher loading than some other polymers. ROMP is known for theproduction of functionalised polymers for organic synthesis (Barrett etal Chemical Reviews 2002 102 pp 3301-24). Suitable ROMP based polymersof formula (IVd) may be prepared by condensation of commerciallyavailable ketone alkene with furan followed by polymerisation, as shownin scheme 2:

In a further aspect of the invention, there is provided a process forpurifying a radiolabelled product which comprises use of a solid-supportbound dipolar scavenger group. This process comprises the steps of(a) contacting a solution-phase mixture of a radiolabelled product offormula (IIIe) and a by-product (VIIe):

wherein the by-product (VIIe) contains an unwanted double bond, formedby an elimination side-reaction, and R*^(e) in the compound of formula(IIIe) is radiohalo, particularly [¹⁸F]fluoro;with a compound of formula (IVe):

wherein Z^(e) is a 1,3-dipole such as —N═N⁺═N⁻ or —C≡N⁺—O⁻such that the compounds of formula (IVe) and (VIIe) may form a covalentbond to each other; and(b) separation of purified radiolabelled product of formula (IIIe) inthe solution phase.

This aspect of the invention has particular relevance to synthesis of3′-deoxy-3′-fluorothymidine ([¹⁸F]-FLT) (IIIe) wherein a commonby-product (VIIe) is formed by elimination of [¹⁸F]HF from the sugarring as shown in scheme 2:

wherein each PG is hydrogen or a hydroxyl protecting group (suitablytert-butoxycarbonyl, benzyl, triphenylmethyl, ordimethoxytriphenylmethyl), and —X^(e)Y^(e) is a suitable leaving groupsuch as an alkyl- or aryl-sulphonate ester (for example trifluoromethanesulphonate, methane sulphonate, or toluene-para-sulphonate) or halo(such as iodo or bromo).

Purification using a compound of formula (IVe):

wherein Z^(e) is a 1,3-dipole -A-E⁺-G⁻, such as —N═N⁺═N⁻ or —C≡N⁺—O⁻,gives a compound of formula (Ve) as shown in scheme 3:

In a further aspect of the invention, a scavenger resin such as acompound of formula (IV) may also be used to react covalently with anyunreacted radiolabelling agent of formula (II) as shown in scheme 4 togive compounds of formula (VI). This purification process may be usedinstead of, or in addition to, processes described herein for removal ofexcess precursor.

Thus, for example:(i) A solid-support bound aldehyde or ketone scavenger group, such as acompound of formula (IVd) may facilitate removal of unreacted aminofunctionalised radiolabelling agent, such as a compound of formula (IIc)from a reaction mixture resulting in a compound of formula (VId):

(ii) A solid-support bound amino scavenger group, such as a compound offormula (IVc) may facilitate removal of unreacted radiolabelling agenthaving an aldehyde or ketone functionality resulting in a compound offormula (VIc).

wherein A and B are as defined for the compound of formula (Vc).(iii) A solid-support bound haloacetyl scavenger group, such as compoundof formula (IVf)

may be used wherein Z^(f) is Cl—CH₂—CO— or another haloacetyl containingmoiety for removal of unreacted radiolabelling agent containing a thiolmoiety of formula (II) from a reaction mixture results in compound offormula (VIf).

Radiotracers, such as [¹⁸F]FDG are now often prepared on an automatedradiosynthesis apparatus using nucleophilic radiofluorination chemistrywith ¹⁸F—, based on the reagent Kryptofix™ 2.2.2. There are severalexamples of such apparatus commercially available, including TracerlabMX (Coincidence Technologies SA) and Tracerlab FX (Nuclear InterfaceGmbH). Such apparatus commonly comprises a cassette, often disposable,in which the radiochemistry is performed, which is fitted to theapparatus in order to perform a radiosynthesis. The cassette normallyincludes fluid pathways, a reaction vessel, and ports for receivingreagent vials as well as any solid-phase extraction cartridges(typically C₁₈ or alumina) used in post-radiosynthetic clean up steps.The methods of the present invention may offer particular advantages inthe field of automated radiosynthesis.

According to a further aspect of the invention, there is provided anautomated radiosynthesis apparatus comprising a vessel, such as acartridge, containing a solid-support bound scavenger group of formula(IV), (IVa), (IVb), (IVc), (IVd), (IVe), or (IVf).

The vessel, such as a cartridge, containing a solid-support boundscavenger group of formula (IV) may be housed in a disposable orremovable cassette designed for use with the automated radiosynthesisapparatus. Therefore, the invention further provides a cassette for anautomated radiosynthesis apparatus comprising a vessel, such as acartridge, containing a solid-support bound scavenger group of formula(IV), (IVa), (IVb), (IVc), (IVd), (IVe), or (IVf).

The invention will now be illustrated by way of the followingnon-limiting examples.

EXAMPLES Example 1 Use of an Isocyanate Resin for Purification of a¹¹C-Tracer

In both cases isocyanate resin was conditioned, using the same solventas that from which precursor was to be extracted. Extraction efficiencywas determined using HPLC. For studies using non-radioactive standardsolutions, xylene was used as a control such that adjustments could bemade for non-specific extraction and solvent loss.

Example 1(a) In Situ Resin Conditioning and Solid Phase Extraction (SPE)at Elevated Temperatures

A cartridge (internal volume 0.067 ml) made of 3.2 mm (⅛″) o.d. steeltubing and circular frits was charged with 25 mg of dry isocyanatefunctionalised polystyrene resin (Novabiochem). Solvent ca 5 ml(dichloromethane (DCM), N,N-dimethylformamide (DMF) ordimethylsulphoxide (DMSO)) was then passed through the cartridge andexcess solvent removed with compressed air. For studies at elevatedtemperature a two-piece heater block, thermocouple and band heater werefitted around the cartridge and the entire assembly left ca 10 min tothermally equilibrate. 500 μl of solution containing precursor2-Pyridin-4-yl-quinoline-8-carboxylic acid (2-methylamino-ethyl)-amide(A) 0.5 mg and Xylene 1.3 mg were then passed through the cartridgeusing a syringe drive. Using this method, SPE efficiency was dependenton the solvent used, with extraction efficiency decreasing in the orderDCM (67%), DMF (36%), and DMSO (<5%) at room temperature.

Example 1(b) SPE with External Resin Conditioning

For external conditioning 300 mg of isocyanate resin (Novabiochem) wassuspended in excess solvent ca 9 ml for ca 5 min. The conditioned resinslurry was then loaded onto a 0.8 ml volume cartridge made of 6 mm (2/8″) steel tubing. Excess solvent was removed with compressed air.Precursor solutions 300 μl or reaction mixture from automated preps 300μl were passed through the cartridge using a syringe drive. A 1 mlsyringe gave flow rates of 0.4 ml min⁻¹, equating to a contact time ca 2min.

Example 1(c) SPE Purification of [¹¹C—CH₃]2-Pyridin-4-yl-quinoline-8-carboxylic acid (2-dimethylamino-ethyl)-amidereaction mixtures

Following [¹¹C]radiolabelling, 300 μl of the resulting reaction mixture(A+B) was drawn up from the reaction vial and dispensed (using a syringedrive) at a flow of 444 μl min⁻¹ through one of the conditionedisocyanate resin cartridges detailed in Examples 1(a) and 1(b). Thecartridge was then flushed with 500 μl of chloroform and the combinedsolutions analysed by HPLC. The cartridge was then flushed with afurther 3 aliquots of 500 μl chloroform. Cumulative product recoveryafter SPE using the external conditioning method of Example 1(b) was 90%with precursor levels at circa 4% of the levels found in thenon-purified reaction mixture.

1. A process for purifying a radiolabelled product which comprises useof a solid-support bound scavenger group of formula (IV):

wherein Z is a scavenger group and SP is a solid support.
 2. A processcomprising the steps of: (a) contacting a solution-phase mixture of aradiolabelled product of formula (III) and excess precursor of formula(I):

wherein XY is a functional group and R* is a radioisotope orradiolabelled portion; with a compound of formula (IV):

wherein Z is a scavenger group; such that the compounds of formulae (IV)and (I) may form a covalent bond to each other; (b) separation ofpurified radiolabelled product of formula (III) in the solution phase.3. A process according to claim 1 wherein the scavenger group Z is anisocyanate, isothiocyanate, thiol, hydrazine, hydrazide, aminooxy,1,3-dipole, aldehyde or ketone.
 4. A process according to claim 1comprising the steps of: (a) contacting a solution-phase mixture of aradiolabelled product of formula (IIIa) and excess precursor of formula(Ia):

wherein R¹ is C₁₋₆ alkyl and R* is [¹¹C]—C₁₋₆alkyl, such as —¹¹CH₃ or[¹⁸F]fluoro C₁₋₆ alkyl or [¹⁸F]fluoro C₆₋₁₂ aryl; with a compound offormula (IVa):

wherein R² is oxygen or sulphur such that the compounds of formulae(IVa) and (Ia) may form a covalent bond to each other; and (b)separation of purified radiolabelled product of formula (IIIa) in thesolution phase.
 5. A process according to claim 1 comprising the stepsof: (a) contacting a solution-phase mixture of a radiolabelled productof formula (IIIb) and excess precursor of formula (Ib):

wherein either (i) the functional group —X^(b)Y^(b) in the compound offormula (Ib) is —OSO₂R³ wherein R³ is C₁₋₁₅ alkyl or C₁₋₁₀ alkylaryl andR³ is optionally substituted by halo (preferably fluoro), for example R³is methyl, para-toluene, trifluoromethyl, and R*^(b) in the compound offormula (IIIb) is a radiohalogen such as radiofluoro (for example ¹⁸F)or radioiodo (such as ¹²³I, ¹²⁴I, or ¹²⁵I) or radiobromo (such as ⁷⁶Br);or (ii) the functional group —X^(b)Y^(b) in the compound of formula (Ib)is —C(O)CH₂Cl and R*^(b) in the compound of formula (IIIb) is—S-L^(b)-^(n)F wherein L^(b) is a C₁₋₃₀ hydrocarbyl linker groupoptionally including 1 to 10 heteroatoms; and ^(n)F is a radioisotope offluorine such as ¹⁸F; with a compound of formula (IVb):

wherein R⁴ is hydrogen; such that the compounds of formulae (IVb) and(Ib) may form a covalent bond to each other; (b) separation of purifiedradiolabelled product of formula (IIIb) in the solution phase.
 6. Aprocess according to claim 1 comprising the steps of: (a) contacting asolution-phase mixture of a radiolabelled product of formula (IIIc) andexcess precursor of formula (Ic):

wherein the functional group —X^(c)Y^(c) in the compound of formula (Ic)is an aldehyde or ketone and R*^(c) in the compound of formula (IIIc) is═N—W-Linker-F where W is C₁₋₁₅ alkyl or C₇₋₁₅ aryl, with a compound offormula (IVc):

wherein Z^(c) is selected from —NH₂, hydrazine, hydrazide, aminooxy,phenylhydrazines, semicarbazide, or thiosemicarbazide; such that thecompounds of formulae (IVc) and (Ic) may form a covalent bond to eachother; and (b) separation of purified radiolabelled product of formula(IIIc) in the solution phase.
 7. A process according to claim 1comprising the steps of: (a) contacting a solution-phase mixture of aradiolabelled product of formula (IIIc) and excess precursor of formula(Ic):

wherein the functional group —X^(c)Y^(c) in the compound of formula (Ic)is —OSO₂R³ wherein R³ is C₁₋₁₅ alkyl or C₁₋₁₀ alkylaryl and R³ isoptionally substituted by halo (preferably fluoro), for example R³ ismethyl, para-toluene, trifluoromethyl and R*^(c) in the compound offormula (IIIc) is ═N—W-Linker-F where W is C₁₋₁₅ alkyl or C₇₋₁₅ aryl,with a compound of formula (IVci):

where W is selected from C₁₋₁₅ alkyl or C₇₋₁₅ aryl, —NH—, —NH—CO— or—O—; such that the compounds of formulae (IVci) and (Ic) may form acovalent bond to each other; and (b) separation of purifiedradiolabelled product of formula (IIIc) in the solution phase.
 8. Aprocess according to claim 1 comprising the steps of: (a) contacting asolution-phase mixture of a radiolabelled product of formula (IIId) andexcess precursor of formula (Id):

wherein the functional group —X^(d)Y^(d) in the compound of formula (Id)is an amine, hydrazine, hydrazide, aminooxy, phenylhydrazine, orsemicarbazide, thiosemicarbazide group and R*^(d) in the compound offormula (IIId) is ═CH-Linker-F where the linker comprises an alkyl, arylor polyethylene glycol component; with a compound of formula (IVd):

wherein Z^(d) is an aldehyde or ketone moiety; such that the compoundsof formulae (IVd) and (Id) may form a covalent bond to each other; and(b) separation of purified radiolabelled product of formula (IIId) inthe solution phase.
 9. A process according to claim 8 wherein thecompound of formula (IVd) has a ketone scavenging group based on aring-opening metathesis polymerisation (ROMP) polymer backbone.
 10. Aprocess according to claim 1 comprising the steps of (a) contacting asolution-phase mixture of a radiolabelled product of formula (IIIe) anda by-product (VIIe):

wherein the by-product (VIIe) contains an unwanted double bond, formedby an elimination side-reaction, and R*^(e) in the compound of formula(IIIe) is radiohalo, particularly [¹⁸F]fluoro; with a compound offormula (IVe):

wherein Z^(e) is a 1,3-dipole such as —N═N⁺═N⁻ or —C≡N⁺—O⁻ such that thecompounds of formula (IVe) and (VIIe) may form a covalent bond to eachother; and (b) separation of purified radiolabelled product of formula(IIIe) in the solution phase.
 11. A process according to claim 10wherein the compound of formula (IIIe) and (VIIe) are:

wherein each PG is hydrogen or a hydroxyl protecting group (suitablytert-butoxycarbonyl, benzyl, triphenylmethyl, ordimethoxytriphenylmethyl).
 12. A process according to claim 1 whichcomprises use of a compound of formula (IVf):

wherein Z^(f) is Cl—CH₂—CO— or another haloacetyl containing moiety forremoval of unreacted radiolabelling agent containing a thiol moiety froma reaction mixture resulting in formation of a compound of formula(VIf):

wherein R* is a is a radioisotope or radiolabelled portion.
 13. Anautomated radiosynthesis apparatus, or a cassette therefor, comprising avessel, such as a cartridge, containing a solid-support bound scavengergroup of formulas comprising: